Two billion people are infected with Mycobacterium tuberculosis worldwide, leading to over 9 million new tuberculosis (TB) cases each year and nearly 2 million deaths. A considerable obstacle to TB control is the emergence of multidrug-resistant (MDR) disease: there are nearly 500,000 new cases of MDR-TB each year. MDR-TB is much more difficult and expensive to treat than drug-susceptible TB, and requires up to 2 years of therapy with a combination of drugs, including second-line antituberculars that are both less potent and more toxic than the first-line TB drugs. The overall goal of this application is to plan a Phase 2 clinical trial to evaluate a lead TB drug candidate, SQ109, for the treatment of MDR-TB. SQ109 completed Phase 1a and Phase 1b human safety studies and was found to be safe and well-tolerated in normal, healthy adults. Sequella belongs to the Pan African Consortium for the Evaluation of Anti-TB Antibiotics (PanACEA), which will evaluate SQ109 in extended EBA and additional phase 2 and 3 studies in TB patients beginning in fall 2010. The objectives of the trial are to evaluate the safety and efficacy of SQ109 in combination with 18 months of Optimized Background Therapy, as well as shortened regimens. The primary endpoint is satisfactory treatment outcome, defined as the absence of treatment failure, relapse, death, or default. We propose to perform this trial in the former Soviet States/Eastern Europe because this region has some of the highest rates of MDR-TB in the world: approximately 10% of new cases and 25% of re-treatment cases are MDR-TB. The present R34 Grant Application will allow us to complete the planning and design of this trial. Specifically, this grant will provide invaluable support to accomplish the following specific aims: Specific Aim 1. We will identify and select collaborators, enrollment sites, and local laboratories. Specific Aim 2. We will finalize the clinical trial protocol, statistical analysis plan, data management plan, and informed consent forms. We will also select a clinical research organization for the study and obtain approval from the relevant local regulatory bodies and Institutional Review Boards. SQ109 is a new TB drug with a novel mechanism of action and potent activity against both drug-sensitive and drug-resistant Mtb. Because of these qualities, it could be an important new tool in the arsenal to control MDR- TB. In addition to the inherent innovation of this drug candidate, we propose to perform an adaptive trial design that will allow us to more rapidly identify the appropriate dose of SQ109 for the treatment of MDR-TB. PUBLIC HEALTH RELEVANCE: Two billion people are infected with Mycobacterium tuberculosis worldwide, leading to over 9 million new tuberculosis (TB) cases each year and nearly 2 million deaths. A considerable obstacle to TB control is the emergence of multidrug-resistant (MDR) disease: there are nearly 500,000 new cases of MDR-TB each year. The goal of this application is to plan a clinical trial to evaluate the TB drug candidate SQ109 for the treatment of MDR-TB.